Despite the availability of potent chemotherapy regimens, such as 5-fluorouracil, folinic acid, irinotecan, and oxaliplatin (FOLFIRINOX) and nab-paclitaxel plus gemcitabine, treatment outcomes in metastatic pancreatic cancer (PC) remain unsatisfactory. The presence of an abundant fibrous stroma in PC is considered a crucial factor for its unfavorable condition. Apparently, stroma acts as a physical barrier to restrict intratumoral cytotoxic drug penetration and creates a hypoxic environment that reduces the efficacy of radiotherapy. In addition, stroma plays a vital supportive role in the development and progression of PC, which has prompted researchers to assess the potential benefits of agents targeting several cellular (e.g., stellate cells) and acellular (e.g., hyaluronan) elements of the stroma. This study aims to briefly review the primary structural properties of PC stroma and its interaction with cancer cells and summarize the current status of anti-stromal therapies in the management of metastatic PC.